Post-traumatic stress disorder (PTSD) is a common problem in humans exposed to traumatic situations with combat US Armed Services personnel having a risk of up to 25%. Thus, PTSD is a major medical problem for the medical system of the Department of Veterans Affairs. Patients with PTSD carry risk of other medical problems, including systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease, and multiple sclerosis. In addition, abnormally high numbers of Th17 T cells are found in the peripheral blood of these patients as are high levels of IL-17. Th17 T cells are critical for the pathogenesis of several autoimmune diseases, and there is increased expression of interferon genes in peripheral blood mononuclear cells (PMBC) prior to onset of PTSD, a condition also seen in autoimmune disease. Data indicate that autoantibodies precede clinical disease by many years, even decades. Thus, we hypothesize that PTSD patients, who are at increased risk of autoimmune disease, will have autoantibodies present in their sera even without clinical autoimmune disease. Preliminary data suggest this is correct. We studied 20 PTSD patients and compared these to 20 patients with mild traumatic brain injury. All were Afghanistan War combat veterans. We found 3 of the PTSD subjects had high titer autoantibodies ? anti-Ro in one, anti-RNP in another and anti-RNP with anti-dsDNA in a third, while another 6 had a positive ANA. In addition, we found autoimmune rheumatic disease increased among 137 subjects with PTSD and mild traumatic brain injury (TBI) compared to 92 with TBI only. Thus, considering the published data concerning immune abnormalities and autoimmune disease in PTSD along with our preliminary data, there is a compelling premise to the proposed studies. We will study subjects with PTSD, comparing these results to matched subjects with other psychiatric diagnoses as well as to subjects with no psychiatric diagnosis, controlled for depression and TBI. We will pursue three specific aims. First, we will determine whether autoantibodies are present in the sera of PTSD subjects and if presence of autoantibodies correlates with the interferon signature. In a second aim we will determine whether there is polyclonal B cell hyperactivity in PTSD. In the third aim we will determine whether abnormal PBMC phenotype is associated with the presence of autoantibody.